Abstract

Background

Schizophrenia is a highly
heritable, neuropsychiatric disorder characterized by episodic psychosis
and altered cognitive function. Despite success in identifying genetic
variants associated with schizophrenia, there remains uncertainty about
the causal genes involved in disease pathogenesis and how their function
is regulated.

Results

We performed a multi-stage
epigenome-wide association study, quantifying genome-wide patterns of
DNA methylation in a total of 1714 individuals from three independent
sample cohorts. We have identified multiple differentially methylated
positions and regions consistently associated with schizophrenia across
the three cohorts; these effects are independent of important
confounders such as smoking. We also show that epigenetic variation at
multiple loci across the genome contributes to the polygenic nature of
schizophrenia. Finally, we show how DNA methylation quantitative trait
loci in combination with Bayesian co-localization analyses can be used
to annotate extended genomic regions nominated by studies of
schizophrenia, and to identify potential regulatory variation causally
involved in disease.

Conclusions

This study represents the
first systematic integrated analysis of genetic and epigenetic variation
in schizophrenia, introducing a methodological approach that can be
used to inform epigenome-wide association study analyses of other
complex traits and diseases. We demonstrate the utility of using a
polygenic risk score to identify molecular variation associated with
etiological variation, and of using DNA methylation quantitative trait
loci to refine the functional and regulatory variation associated with
schizophrenia risk variants. Finally, we present strong evidence for the
co-localization of genetic associations for schizophrenia and
differential DNA methylation.